U.S. patent application number 10/655645 was filed with the patent office on 2004-07-15 for processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1h-benzimidazoles.
Invention is credited to Avrutov, Ilya, Finkelstein, Nina, Mendelovici, Marioara.
Application Number | 20040138466 10/655645 |
Document ID | / |
Family ID | 32718861 |
Filed Date | 2004-07-15 |
United States Patent
Application |
20040138466 |
Kind Code |
A1 |
Avrutov, Ilya ; et
al. |
July 15, 2004 |
Processes for the production of substituted 2-(2-pyridylmethyl)
sulfinyl-1H-benzimidazoles
Abstract
Improved processes for preparing substituted
2-(2-pyridylmethyl)sulfinyl-1- H-benzimidazoles are disclosed.
Inventors: |
Avrutov, Ilya; (Ontario,
CA) ; Mendelovici, Marioara; (Rechovot, IL) ;
Finkelstein, Nina; (Herzliya, IL) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
32718861 |
Appl. No.: |
10/655645 |
Filed: |
September 4, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10655645 |
Sep 4, 2003 |
|
|
|
10066850 |
Feb 4, 2002 |
|
|
|
60408163 |
Sep 4, 2002 |
|
|
|
60266162 |
Feb 2, 2001 |
|
|
|
Current U.S.
Class: |
546/273.7 |
Current CPC
Class: |
C07D 401/12
20130101 |
Class at
Publication: |
546/273.7 |
International
Class: |
C07D 43/02 |
Claims
What is claimed is:
1. A process for preparing a thioester compound having formula A:
8wherein R.sub.1 is methyl, R.sub.2 is 2-trifluoroethoxy, R.sub.3
is hydrogen and R.sub.4 is hydrogen, comprising the steps of: a)
reacting a thioether compound of formula B 9wherein R.sub.1 through
R.sub.4 are as in formula A, with tert-butyl hydroperoixde in the
presence of vanadium acetylacetonate in ethanol to produce
selective oxidation of the thioether compound of formula B to form
the thioester compound of formula A; and b) isolating the thioester
compound of formula A, wherein the tert-butyl hydroperoixde is
present in a mol/mol ratio of tert-butyl hydroperoxide to the
compound of formula B of about 1.15 to about 4.5, and the vanadium
acetylacetonate is present in a mole/mol ratio of vanadium
acetylacetonate to the compound of formula B of about 0.01 to about
0.6.
2. The process of claim 1, wherein the tert-butyl hydroperoixde is
present in a mol/mol ratio of tert-butyl hydroperoxide to the
compound of formula B of about 1.96 and the vanadium
acetylacetonate is present in a mole/mol ratio of vanadium
acetylacetonate to the compound of formula B of about 0.015.
3. The process of claim 1, wherein the oxidation is performed at
about 5.degree. C.
4. The process of claim 1, wherein the oxidation is performed for
about 6 hours.
5. The process of claim 1, after the reacting step of a), further
comprising the step of: a') neutralizing the
tert-butylhydroperoxide.
6. The process of claim 5, wherein the neutralizing step is
performed by adding sodium sulfite.
7. The process of claim 1, wherein the isolating step is performed
by vacuum filtration followed by drying.
8. A process for preparing a thioester compound of formula A:
10wherein R.sub.1, R.sub.2, and R.sub.4 are each selected from the
group consisting of hydrogen, substituted or unsubstituted lower
alkyl and substituted lower alkoxy; and R.sub.3 is selected from
the group consisting of hydrogen and substituted or unsubstituted
lower alkyl, comprising reacting a thioether compound of formula B
11wherein R.sub.1 through R.sub.4 are as in formula A, with an
oxidizing agent selected from the group consisting of tert-butyl
hydroperoxide in the presence of a catalyst, OXONE.RTM. and
potassium peroxymonosulfate to produce selective oxidation of the
thioether compound of formula B to form the thioester compound of
formula A.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This continuation-in-part application claims priority to the
provisional application Serial No. 60/408,163 filed Sep. 4, 2002
and to the U.S. application Ser. No. 10/066,850 filed Feb. 4, 2002,
which in turn claims priority to the provisional application Serial
No. 60/266,162 filed Feb. 2, 2001; the disclosures of which are
incorporated by reference in their entirety herein.
FIELD OF THE INVENTION
[0002] The present invention relates to novel processes of
preparing substituted 2-(2-pyridylmethyl)
sulfinyl-1H-benzimidazoles.
BACKGROUND OF THE INVENTION
[0003] Several substituted
2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are known gastric
proton pump inhibitors. These include omeprazole
(5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)
methyl]sulfinyl]-1H-ben- zimidazole), lansoprazole
(2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyri-
dinyl]methyl]sulfinyl]-1H-benzimidazole), pantoprazole
(5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-b-
enzimidazole, and rabeprazole
(2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyidi-
nyl]methyl]sulfinyl]-1H-benzimidazole. For example, omeprazole is a
proton pump inhibitor commercially available for the treatment of
gastric ulcers. The compound is disclosed in European Patent No.
5318.
[0004] The reported synthesis of these substituted
2-(2-pyridylmethyl)sulf- inyl-1H-benzimidazoles principally
involves generally an oxidation process of a thioether moiety to
form a thioester moiety of the compound of formula A: 1
[0005] Various methods employing various different oxidants to
perform this oxidation are known. For example, Canadian Patent No.
1,263,119 describes the use of hydrogen peroxide over a vanadium
catalyst (such as vanadium pentoxide, sodium vanadate and vanadium
acteylacetonate). Canadian Patent No. 1,127,158 similarly describes
the use of peracids, peresters, ozone, etc. European Patent
Application, Publication No. 533,264 describes the use of magnesium
monoperoxyphthalate as the oxidizing agent. PCT Publication No.
WO91/18895 describes the use of m-chloroperoxy benzoic acid as the
oxidizing agent. GB Pat. No. 2,069,492 generally describes this
acid and other peroxy acids in the oxidation of substituted
(phenylthiomethyl)pyridines.
[0006] Use of tert-butyl hydroperoxide (TBHP) as an oxidant has
already been suggested for the performance of various organic
oxidations. Sharpless et al., Aldrichimica Acta 12:63 (1979) review
the use of THBP as an oxidant and compared with hydrogen peroxide
and other peracids. Sharpless et al. describe the use of TBHP in
the epoxidation of olefinic alcohols in the presence of
VO(acac).sub.2 or Mo(CO).sub.5 catalysts. The oxidation of
sulphides, however, is not described.
[0007] In an effort to develop a method for the selective oxidation
of sulphides to sulphoxides, Choudray et al., J. Mol. Catalysts,
75:L7-L12 (1992) describe the use of TBHP in the presence of
vanadium pillared clay. The results demonstrated selectivity for
the oxidation to sulphoxide in preference to the sulphone far
superior to that of known TBHP/vanadium catalysts. The use of
VO(acac).sub.2 or V.sub.2O.sub.5 resulted in sulphones rather than
sulfoxide predominating in the final product.
[0008] There has been a long felt need for efficient and safe
methods for the selective oxidation of a thioether moiety of
formula B to a thioester moiety of formula A. The present invention
provides efficient and safe methods of preparing various
substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles.
SUMMARY OF THE INVENTION
[0009] The present invention provides a process for preparing a
thioester compound of formula A: 2
[0010] wherein R.sub.1, R.sub.2, and R.sub.4 are each selected from
the group consisting of hydrogen, substituted or unsubstituted
lower alkyl and substituted or unsubstituted lower alkoxy; and
R.sub.3 is selected from the group consisting of hydrogen and
substituted or unsubstituted lower alkyl, comprising reacting a
thioether compound of formula B 3
[0011] wherein R.sub.1 through R.sub.4 are as in formula A, with an
oxidizing agent to produce selective oxidation of the thioether
compound of formula B to form the thioester compound of formula
A.
[0012] The present invention further provides a process for
preparing a thioester compound of compound of formula A, comprising
reacting a thioether compound of formula B with Oxone.RTM. (Oxone
monopersulphate).
[0013] The present invention further provides a process for
preparing a thioester compound of compound of formula A, comprising
reacting a thioether compound of formula B with tert-butyl
hydroperoxide (TBHP) in the presence of a catalyst selected from
the group consisting of vanadyl (IV) acetylacetonate, sodium
metavanadate and vanadium pentoxide.
[0014] The present invention provides a process for preparing a
thioester compound having formula A: 4
[0015] wherein R.sub.1 is methyl, R.sub.2 is 2-trifluoroethoxy,
R.sub.3 is hydrogen and R.sub.4 is hydrogen, comprising the steps
of:
[0016] a) reacting a thioether compound of formula B 5
[0017] wherein R.sub.1 through R.sub.4 are as in formula A, with
tert-butyl hydroperoixde in the presence of vanadium
acetylacetonate in ethanol to produce selective oxidation of the
thioether compound of formula B to form the thioester compound of
formula A; and
[0018] b) isolating the thioester compound of formula A.
[0019] Preferably, the tert-butyl hydroperoixde is present in a
mol/mol ratio of tert-butyl hydroperoxide to the compound of
formula B of about 1.15 to about 4.5, and the vanadium
acetylacetonate is present in a mole/mol ratio of vanadium
acetylacetonate to the compound of formula B of about 0.01 to about
0.6.
[0020] More preferably, the tert-butyl hydroperoixde is present in
a mol/mol ratio of tert-butyl hydroperoxide to the compound of
formula B of about 1.96 and the vanadium acetylacetonate is present
in a mole/mol ratio of vanadium acetylacetonate to the compound of
formula B of about 0.015.
[0021] Preferably, the oxidation is performed at about 5.degree. C.
and for about 6 hours.
[0022] Preferably, after the reacting step of a), further
comprising the step of neutralizing the tert-butylhydroperoxide.
Preferably, the neutralizing step is performed by adding sodium
sulfite. Preferably, the isolating step is performed by vacuum
filtration followed by drying.
[0023] The substituted
2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles prepared according to
the process of the present invention yield the desired products in
a relatively high yield with only small amounts of the
corresponding sulphone as by-product.
[0024] An object of the present invention is to provide an improved
process of selective oxidation of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
-pyridyl)methyl]thio]-1H-benzimidazole (MPB) that utilizes a
non-hazardous oxidant and results in the selective production of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzi-
midazole (omeprazole), i.e., the corresponding sulphoxide, with
only minor amounts of 5-methoxy-2
[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]
sulphonyl]benzimidazole.
[0025] Another object of the present invention is to provide an
improved process of selective oxidation of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy-
)-2-pyridinyl]methyl]thio]-1H-benzimidazole that utilizes a
non-hazardous oxidant and results in the selective production of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H--
benzimidazole (lansoprazole), i.e., the corresponding sulphoxide,
with only minor amounts of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridiny-
l]methyl]sulphonyl]-1H-benzimidazole.
[0026] Another object of the present invention is to provide an
improved process of selective oxidation of
5-(difluoromethoxy)-2-[[(3,4-dimethoxy--
2-pyridinyl)methyl]thio]-1H-benzimidazole that utilizes a
non-hazardous oxidant and results in the selective production of
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-be-
nzimidazole (pantoprazole), i.e., the corresponding sulphoxide,
with only minor amounts of
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methy-
l]sulphonyl]-1H-benzimidazole.
[0027] Another object of the present invention is to provide an
improved process of selective oxidation of
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-p-
yidinyl]methyl]thio]-1H-benzimidazole that utilizes a non-hazardous
oxidant and results in the selective production of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzi-
midazole (rabeprazole), i.e., the corresponding sulphoxide, with
only minor amounts of
5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]
sulphonyl]-1H-benzimidazole.
[0028] Another object of the present invention is to provide an
improved process of preparing omeprazole while the amount of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphonyl]-1H-benz-
imidazole (SOMP) as by-product when the reaction proceeds to
completion, is typically within the range of about 1 to about 4.5%
by weight of the crude product mixture.
[0029] Another object of the present invention is to provide an
improved process of preparing lansoprazole while the amount of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulphonyl]-1H-
-benzimidazole as by-product when the reaction proceeds to
completion, is typically within the range of about 1 to about 4.5%
by weight of the crude product mixture.
[0030] Another object of the present invention is to provide an
improved process of preparing pantoprazole while the amount of
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)
methyl]sulphonyl]-1H-benzimidazole as by-product when the reaction
proceeds to completion, is typically within the range of about 1 to
about 4.5% by weight of the crude product mixture.
[0031] Another object of the present invention is to provide an
improved process of preparing rabeprazole while the amount of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)
methyl]sulphonyl]-1H-benzimidazole as by-product when the reaction
proceeds to completion, is typically within the range of about 1 to
about 4.5% by weight of the crude product mixture.
DETAILED DESCRIPTION OF THE INVENTION
[0032] Definitions: As used herein, the following abbreviations are
used: "VO(acac).sub.2" is vanadium bis acetylacetonate; "TBHP" is
tert-butyl hydroperoxide; "NaVO.sub.3" is sodium meta-vanadate;
"V.sub.2O.sub.5" is vanadium pentoxide; "MPB" is
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyri-
dyl)methyl]thio]benzimidazole; "OMP" is omeprazole; "SOMP" is
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphonyl]-1H-benz-
imidazole; "Oxone.RTM." refers to a trademark name of an oxidizing
agent under Du Pont for an acidic, white, granular, free-flowing
solid containing the active ingredient potassium peroxymonosulfate;
"TBAB" is tert-butyl ammonium bromide which is a quaternary
ammonium salt that is one of the most common phase transfer
catalysts; "substantially free" refers to sulphone by-product less
than about 1 to about 4.5% by weight of the crude product
mixture.
[0033] The present invention provides a process for preparing a
thioester compound of formula A: 6
[0034] wherein R.sub.1, R.sub.2, and R.sub.4 are each selected from
the group consisting of hydrogen, substituted or unsubstituted
lower alkyl and substituted or unsubstituted lower alkoxy; and
R.sub.3 is selected from the group consisting of hydrogen and
substituted or unsubstituted lower alkyl, comprising reacting a
thioether compound of formula B 7
[0035] wherein R.sub.1 through R.sub.4 are as in formula A, with an
oxidizing agent to produce selective oxidation of the thioether
compound of formula B to form the thioester compound of formula
A.
[0036] Preferably, the present invention provides the preparation
of substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles of
formula A, wherein R.sub.1 is methyl; R.sub.2 is methoxy; R.sub.3
is methyl and R.sub.4 is methoxy. The compound is omeprazole.
[0037] Preferably, the present invention provides the preparation
of substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles of
formula A, wherein R.sub.1 is methyl; R.sub.2 is 2-trifluoroethoxy;
R.sub.3 is hydrogen and R.sub.4 is hydrogen. The compound is
lansoprazole.
[0038] Preferably, the present invention provides the preparation
of substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles of
formula A, wherein R.sub.1 is methoxy; R.sub.2 is methoxy; R.sub.3
is hydrogen and R.sub.4 is difluoromethoxy. The compound is
pantoprazole.
[0039] Preferably, the present invention provides the preparation
of substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles of
formula A, wherein R.sub.1 is methyl; R.sub.2 is
MeOCH.sub.2CH.sub.2CH.sub.2O, R.sub.3 is hydrogen and R.sub.4 is
hydrogen. The compound is rabeprazole.
[0040] According to one embodiment, the oxidation is performed with
tert-butyl hydroperoxide (TBHP) in the presence of a catalyst
selected from the group consisting of vanadyl bis-acetylacetonate,
sodium meta-vanadate and vanadium pentoxide. Preferably, the
catalyst is vanadyl bis-acetylacetonate.
[0041] According to another embodiment, the molar ratio of
tert-butyl hydroperoxide (TBHP) to a compound of formula B, is in
the range of about 1.15 to about 4.5. Preferably, the compound of
formula A includes
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimida-
zole,
2[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio]-1H--
benzimidazole,
5-(difluoromethoxy)-2-[[3,4-dimethoxy-2-pyridinyl)methyl]th-
io]-1H-benzimidazole, and
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]-
methyl]thio]-1H-benzimidazole.
[0042] According to another embodiment, the molar ratio of vanadyl
bis-acetylacetonate to the compound of formula B is from about 0.01
to about 0.6.
[0043] According to another embodiment, the oxidation by tert-butyl
hydroperoxide (TBHP) in the presence of a catalyst is performed in
an organic solvent selected from the group consisting of toluene,
lower alkanols and ethyl acetate.
[0044] Another preferred embodiment of the present invention is
that the oxidation is performed in an organic solvent such as
toluene, a lower alkanol, preferably isopropanol or ethyl acetate.
Most preferable solvent is toluene or isopropanol.
[0045] Preferably, the oxidation of substituted
2-(2-pyridylmethyl)sulfiny- l-1H-benzimidazoles of formula A is
performed at temperature ranging from about -10.degree. C. to about
30.degree. C.
[0046] Preferably, the oxidation of substituted
2-(2-pyridylmethyl)sulfiny- l-1H-benzimidazoles of formula A is
performed over a period of about 2 to about 10 hours.
[0047] According to another embodiment, the oxidation is performed
in the presence of Oxone.RTM. (Oxone monopersulphate).
[0048] According to another embodiment, the molar ratio between
Oxone.RTM. (Oxone monopersulphate) and the compound of formula B is
from about 1.25 to about 1.6:1, most preferably about 1.4 to about
1.6:1.
[0049] According to another embodiment, the oxidation by Oxone.RTM.
(Oxone monopersulphate) is performed in the presence of an aqueous
organic solvent. Preferably, the organic solvent is acetone,
methanol or in two-phase system (CH.sub.2Cl.sub.2/H.sub.2O, (ethyl
acetate/H.sub.2O) in the presence of phase-transferred catalyst
(e.g. TBAB). More preferably, the oxidation is performed in about
5% aqueous methanol.
[0050] Preferably, the oxidation of substituted
2-(2-pyridylmethyl)sulfiny- l-1H-benzimidazoles of formula A is
performed in a two-phase system selected from
(CH.sub.2Cl.sub.2/H.sub.2O) and (ethyl acetate/H.sub.2O).
[0051] Preferably, the oxidation of substituted
2-(2-pyridylmethyl)sulfiny- l-1H-benzimidazoles of formula A is
performed in the presence of tert-butyl ammonium bromide
(TBAB).
[0052] According to another embodiment, the oxidation by Oxone.RTM.
(Oxone monopersulphate) is performed at a temperature ranging from
about -10.degree. C. to about 30.degree. C. over a time period of
about 2 to about 10 hours.
[0053] The oxidation conditions of the present invention result in
the production of the compound of formula A, wherein the amount of
sulphone derivative is less than about 0.5% (wt/wt) of the final
product preferably less than 0.2% (wt/wt).
[0054] Preferably, the pure products prepared in according to the
disclosed method include pantoprazole, lansoprazole, omeprazole and
rabeprazole.
[0055] The invention will now be exemplified by the following
non-limiting Examples.
EXAMPLES
Example 1
Selective Oxidation of
5-methoxy-2-F[(4-methoxy-3,5-dimethyl-2-pyridyl)met-
hyl]thio]-1H-benzimidazole to Form
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
-pyridyl)methyl]sulfinyl-1H-benzimidazole (Omeprazole)
[0056] 1.5 mg (0.6% molar) VO(acac).sub.2) was dissolved in 12 ml
ethanol at room temperature. The solution was stirred and 3 grams
of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole
(MPB) were added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP)
(70%) was added over a 5-minute period at 16-17.degree. C. and the
solution was then stirred for 3 hours. After completion of the
reaction, the product mixture was cooled to about 15.degree. C. and
treated with aqueous sodium metabisulphate. The resultant solid was
filtered off, washed with cooled ethyl acetate to afford the end
product as an almost white solid (2.5 grams, yield 79%).
Example 2
Selective Oxidation of
5-methoxy-2-r[(4-methoxy-3,5-dimethyl-2-pyridyl)met-
hyl]thio]-1H-benzimidazole to Form
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
-pyridyl)methyl]sulfinyl]-1H-benzimidazole (Omeprazole
[0057] 15 mg (0.6% molar) VO(acac).sub.2) in 5 ml toluene were
added to a suspension of 3 grams of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)-
methyl]thio]benzimidazole (MPB) in 30 ml toluene at a temperature
of about 5.degree. C. 3.5 ml of tert-butyl hydroperoxide (TBHP) in
toluene (3M, 115%) were added dropwise, while the temperature was
maintained between 5 and 7.degree. C. Upon completing the addition
of the TBHP, the temperature rose to 22.degree. C. The reaction was
allowed to proceed to completion (about 3 hours), after which the
cooled product mixture was treated with aqueous sodium
metabisulphite. The solid product was filtered off, washed with
cooled ethyl acetate and dried in an oven (yield 80.7%)
Example 3
Selective Oxidation of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridiny-
l]methyl]thio]-1H-benzimidazole to Form
2-[[[3-methyl-4-(2,2,2-trifluoro-e-
thoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole
(Lansoprazole)
[0058] 1.5 mg (0.6% molar) VO(acac).sub.2) is dissolved in 12 ml
ethanol at room temperature. The solution is stirred and 3 grams of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio]-1H-benz-
imidazole are added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP)
(70%) is added over a 5-minute period at 16-17.degree. C. and the
solution is then stirred for 3 hours. After completion of the
reaction, the product mixture is cooled to about 15.degree. C. and
treated with aqueous sodium metabisulphate. The resultant solid is
filtered off, washed with cooled ethyl acetate to afford the end
product as an almost white solid (2.5 grams, yield 79%).
Example 4
Selective Oxidation of
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-
methyl]thio]-1H-benzimidazole to Form
5-(difluoromethoxy)-2-[[(3,4-dimetho-
xy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (Pantoprazole)
[0059] 1.5 mg (0.6% molar) VO(acac).sub.2) is dissolved in 12 ml
ethanol at room temperature. The solution is stirred and 3 grams of
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl]methyl]methyl]thio]-1H-
-benzimidazole are added. 1.5 ml aqueous tert-butyl hydroperoxide
(TBHP) (70%) is added over a 5-minute period at 16-17.degree. C.
and the solution is then stirred for 3 hours. After completion of
the reaction, the product mixture is cooled to about 15.degree. C.
and treated with aqueous sodium metabisulphate. The resultant solid
is filtered off, washed with cooled ethyl acetate to afford the end
product as an almost white solid (2.5 grams, yield 79%).
Example 5
Selective Oxidation of
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyidinyl]meth-
yl]thio]-1H-benzimidazole to Form
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-py-
idinyl]meth]sulfinyl]-1H-benzimidazole (Rabeprazole)
[0060] 1.5 mg (0.6% molar) VO(acac).sub.2) is dissolved in 12 ml
ethanol at room temperature. The solution is stirred and 3 grams of
2-[[[4-(3-methoxy-propxy)-3-methyl-2-pyidinyl]methyl]thio]-1H-benzimidazo-
le are added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP) (70%)
is added over a 5-minute period at 16-17.degree. C. and the
solution is then stirred for 3 hours. After completion of the
reaction, the product mixture is cooled to about 15.degree. C. and
treated with aqueous sodium metabisulphate. The resultant solid is
filtered off, washed with cooled ethyl acetate to afford the end
product as an almost white solid (2.5 grams, yield 79%).
Example 6
Changes of Experimental Conditions and Yields
[0061] The above described processes of Example 1 and Example 2
were repeated while using the conditions given in Table I below, to
give the following results:
1TABLE I Catalyst Type/amount TBHP HPLC of Product Mixture (mol %)
Type/amount Solvent MPB Omeprazole Sulfone Yield %
VO(acac).sub.2/0.6 Dry/115% Toluene 0.1 93.9 0.7 80.7
VO(acac).sub.2/0.6 Aq/115% Toluene 3.0 94.4 1.25 74.6
VO(acac).sub.2/0.25 Dry/150% Toluene 0.6 93.2 1.2 68.5
VO(acac).sub.2/0.08 Aq/150% i-PrOH 0.9 97.2 1.6 83.5
VO(acac).sub.2/0.05 Aq/150% MeOH 1.9 92.1 4.4 >50
VO(acac).sub.2/0.05 Aq/150% EtOH 0.7 95.6 3.3 63
V.sub.20.sub.5silica/0.05 Aq/450% EtOH abs 13.4 82.6 2.4 >50
NaVO.sub.3/0.6 Aq/115% EtOH abs 7.3 87.7 1.9 >50
Example 7
Comparison with the Method disclosed by Canadian Patent
1,263,119
[0062] 4 mg (0.06% molar) VO (acac).sub.2 were added to suspension
of 9 grams of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H--
benzimidazole (MPB) in 66 ml ethanol at room temperature. 35 ml of
35% aqueous hydrogen peroxide (150% mol) was added at room
temperature with no visible exotherm, the mixture was then stirred.
After 12 hours the reaction mixture still contained 65% of
untreated MPB and only 32% omeprazole. Prolongation of the reaction
time did not lead to further production of omeprazole.
Example 8
Selective Oxidation By Oxone.RTM. of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl- -2-pyridyl)
methyl]thio]-1H-benzimidazole to form 5-methoxy-2-[[(4-methoxy-
-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole
(Omeprazole)
[0063] A mixture of 3 grams
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridy- l)methyl]
thio]benzimidazole (MPB), 3 grams NaHCO.sub.3 and 20 ml aqueous
methanol was cooled to -2.degree. C. and 3.5 ml (5.69 mmol)
Oxone.RTM. was added. The mixture was stirred for 4 hours at
0.degree. C. and a further 1 gram (mmol) Oxone.RTM. was added and
stirring continued for 1.5 hours. A solution of 0.8 gram sodium
metabisulfite in 20 ml water was added dropwise over 5-10 minutes.
After further stirring the resultant precipitate was filtered,
washed successively with water and 50% aqueous methanol and
dried.
[0064] Yield 2.7 grams, 84% (purity 98.1%), SOMP 0.15%.
Example 9
Changes of Experimental Conditions and Yields
[0065] The above described reaction of Example 8 was repeated while
using the conditions given in Table II below, to give the following
results:
2TABLE II Oxone .RTM. (equivalents Temp Time to) Solvent (.degree.
C.) (hours) % MPB % OMP % SOMP Yield % 1.25 5% -10(210 30.75 0.6
97.4 0.2 60.0 acetone 1.25 EA/H2O/ -0(5 2 0.2 94.1 -- 50.7 TBAB
1.25 + 0.35 5% -2(3 7.5 0.2 98.1 0.15 84.0 MeOH
Example 10
Selective Oxidation By Oxone.RTM. of
2-[[[3-methyl-4-(2,2,2-trifluoro-etho-
xy)-2-pyridinyl]methyl]thio]-1H-benzimidazole to form of
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H--
benzimidazole (Lansoprazole)
[0066] A mixture of 3 grams
2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyr- idinyl] methyl]
thio]-H-benzimidazole, 3 grams NaHCO.sub.3 and 20 ml aqueous
methanol is cooled to -2.degree. C. and 3.5 ml (5.69 mmol)
Oxone.RTM. is added. The mixture is stirred for 4 hours at
0.degree. C. and a further Igram (mmol) Oxone.RTM. is added and
stirring continues for 1.5 hours. A solution of 0.8 gram sodium
metabisulfite in 20 ml water is added dropwise over 5-10 minutes.
After further stirring the resultant precipitate is filtered,
washed successively with water and 50% aqueous methanol and dried.
Purity is 98.1%.
Example 11
Selective Oxidation By Oxone.RTM. of
5-(difluoromethoxy)-2-[[(3,4-dimethyo-
xy-2-pyridinjyl)methyl]thio]-1H-benzimidazole to form
5-(difluoromethoxy)-2-[[(3,4-dimethyoxy-2-pyridiniyl)methyl]sulfinyl]-1H--
benzimidazole (Pantoprazole)
[0067] A mixture of 3 grams
5-(difluoromethoxy)-2-[[(3,4-dimethyoxy-2-pyri- dinjyl)methyl]
thio]-1H-benzimidazole, 3 grams NaHCO.sub.3 and 20 ml aqueous
methanol is cooled to -2.degree. C. and 3.5 ml (5.69 mmol)
Oxone.RTM. is added. The mixture is stirred for 4 hours at
0.degree. C. and a further 1 gram (mmol) Oxone.RTM. is added and
stirring continues for 1.5 hours. A solution of 0.8 gram sodium
metabisulfite in 20 ml water is added dropwise over 5-10 minutes.
After further stirring the resultant precipitate is filtered,
washed successively with water and 50% aqueous methanol and dried.
Purity is 98.1%.
Example 12
Selective Oxidation By Oxone.RTM. of
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-
-pyridinyl]methyl]thio]-1H-benzimidazole to Form
2-[[[4-(3-methoxy-propoxy-
)-3-methyl-2-pyridinyl]sulfinyl]-1H-benzimidazole (Rabeprazole)
[0068] A mixture of 3 grams
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridiny-
l]methyl]thio]-1H-benzimidazole, 3 grams NaHCO.sub.3 and 20 ml
aqueous methanol is cooled to -2.degree. C. and 3.5 ml (5.69 mmol)
Oxone.RTM. is added. The mixture is stirred for 4 hours at
0.degree. C. and a further 1 gram (mmol) Oxone.RTM. is added and
stirring continued for 1.5 hours. A solution of 0.8 gram sodium
metabisulfite in 20 ml water is added dropwise over 5-10 minutes.
After further stirring the resultant precipitate is filtered,
washed successively with water and 50% aqueous methanol and dried.
Purity is 98.1%.
Example 13
[0069] Into a flask 1L ethanol (95%) was charged and cooled under
stirring to 5.degree. C. Under mixing 200 grams of LNPS
(2-[[3-methyl-4-(2,2,2-tri- fluoroethoxy)-2-pyridinyl]thio]-1H
benzimidazole) and 3 grams vanadium acetyl acetonate were added to
form a suspension. 100 grams tert-butyl-hydroperoxide solution was
dropped into the suspension. The suspension was maintained under
mixing for 6 hours. 40 grams Na.sub.2SO3 (dissolved in 400 mL
water) were added. 1L of water (pH=8-8.5; the pH was realized by
the addition of NH.sub.4OH) was added to the suspension and the
suspension was further mixed for 17 hours at 25.degree. C. The
suspension was cooled to 5.degree. C. The solid phase was separated
by vacuum filtration and was then dried. 178 grams LNP crude was
obtained (yield: 85%). Sulfone: 0.15%.
[0070] The present invention is not to be limited in scope by the
specific embodiments described herein. It will be understood that
various modifications may be made without departing from the spirit
and scope of the invention. The disclosures of cited references
herein are incorporated by reference in their entireties.
* * * * *